Phosphomannomutase deficiency (PMM2-CDG): ataxia and cerebellar assessment

Serrano, Mercedes; Diego, V. de; Muchart, Jordi; Cuadras, Daniel; Felipe, Aida; Macaya, Alfons; Velázquez, Ramón; Poo, M. Pilar; Fons, Carmen; O’Callaghan, Mar; García‐Cazorla, Àngels; Boix, Cristina Martínez; Robles, Bernabé; Carratalá, Francisco Antonio Martínez; Girós, M.; Briones, Paz; Gort, Laura; Artuch, Rafael; Pérez‐Cerdá, Celia; Jaeken, Jaak; Pérez, Belén; Pérez‐Dueñas, Belén

doi:10.1186/s13023-015-0358-y

Cited by 54 publications

(61 citation statements)

References 23 publications

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“…Indeed, cerebellar hypoplasia is an antenatal-onset symptom, occurring early, when the external granule layer—which appears at the end of the embryonic period and persists up to 2 years after birth—is still playing an active germinal role and the development of the cerebellum is still incomplete 22 23. A link between the severity of cerebellar symptoms and neuroimaging findings has, however, been proposed in PMM2-CDG 24. Several autopsy findings show widespread cerebellar atrophy, with the anterior lobe vermis more severely affected 25.…”

Section: Discussionmentioning

confidence: 99%

Clinical, laboratory and molecular findings and long-term follow-up data in 96 French patients with PMM2-CDG (phosphomannomutase 2-congenital disorder of glycosylation) and review of the literature

et al. 2017

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Section: Discussionmentioning

confidence: 99%

Clinical, laboratory and molecular findings and long-term follow-up data in 96 French patients with PMM2-CDG (phosphomannomutase 2-congenital disorder of glycosylation) and review of the literature

et al. 2017

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“…Compound VIII, shows a lipophilicity value (clogP) that predicts good permeability in this respect [Summerfield et al, 2007]. Crossing the blood-brain barrier increases the likelihood of improving the neurological symptoms of PMM2-CDG, such as cerebellar atrophy [Serrano et al, 2015]. However, it should be taken in consideration that glycoproteins are involved in multiple signaling pathways essential in tissue and organ development [Thiel et al, 2006;Grunewald, 2009;Schneider et al, 2012].…”

Section: μMmentioning

confidence: 99%

Pharmacological Chaperoning: A Potential Treatment for PMM2-CDG

et al. 2016

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The congenital disorder of glycosylation (CDG) due to phosphomannomutase 2 deficiency (PMM2-CDG), the most common N-glycosylation disorder, is a multisystem disease for which no effective treatment is available. The recent functional characterization of disease-causing mutations described in patients with PMM2-CDG led to the idea of a therapeutic strategy involving pharmacological chaperones (PC) to rescue PMM2 loss-of-function mutations. The present work describes the high-throughput screening, by differential scanning fluorimetry, of 10,000 low-molecular-weight compounds from a commercial library, to search for possible PCs for the enzyme PMM2. This exercise identified eight compounds that increased the thermal stability of PMM2. Of these, four compounds functioned as potential PCs that significantly increased the stability of several destabilizing and oligomerization mutants and also increased PMM activity in a disease model of cells overexpressing PMM2 mutations. Structural analysis revealed one of these compounds to provide an excellent starting point for chemical optimization since it passed tests based on a number of pharmacochemical quality filters. The present results provide the first proof-of-concept of a possible treatment for PMM2-CDG and describe a promising chemical structure as a starting point for the development of new therapeutic agents for this severe orphan disease.

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“…International Cooperative Ataxia Rating Scale (ICARS) involves a 100-point rating scale in which higher scores denote more evident clinical abnormalities 23. ICARS includes subscores for posture and gait (0–34), kinetic functions (0–52), speech abnormalities (0–8) and oculomotor function (0–6).…”

Section: Introductionmentioning

confidence: 99%

From gestalt to gene: early predictive dysmorphic features of PMM2-CDG

Martinez‐Monseny¹,

Cuadras²,

Bolasell³

et al. 2018

J Med Genet

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IntroductionPhosphomannomutase-2 deficiency (PMM2-CDG) is associated with a recognisable facial pattern. There are no early severity predictors for this disorder and no phenotype–genotype correlation. We performed a detailed dysmorphology evaluation to describe facial gestalt and its changes over time, to train digital recognition facial analysis tools and to identify early severity predictors.MethodsPaediatric PMM2-CDG patients were evaluated and compared with controls. A computer-assisted recognition tool was trained. Through the evaluation of dysmorphic features (DFs), a simple categorisation was created and correlated with clinical and neurological scores, and neuroimaging.ResultsDysmorphology analysis of 31 patients (4–19 years of age) identified eight major DFs (strabismus, upslanted eyes, long fingers, lipodystrophy, wide mouth, inverted nipples, long philtrum and joint laxity) with predictive value using receiver operating characteristic (ROC) curveanalysis (p<0.001). Dysmorphology categorisation using lipodystrophy and inverted nipples was employed to divide patients into three groups that are correlated with global clinical and neurological scores, and neuroimaging (p=0.005, 0.003 and 0.002, respectively). After Face2Gene training, PMM2-CDG patients were correctly identified at different ages.ConclusionsPMM2-CDG patients’ DFs are consistent and inform about clinical severity when no clear phenotype–genotype correlation is known. We propose a classification of DFs into major and minor with diagnostic risk implications. At present, Face2Gene is useful to suggest PMM2-CDG. Regarding the prognostic value of DFs, we elaborated a simple severity dysmorphology categorisation with predictive value, and we identified five major DFs associated with clinical severity. Both dysmorphology and digital analysis may help physicians to diagnose PMM2-CDG sooner.

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Phosphomannomutase deficiency (PMM2-CDG): ataxia and cerebellar assessment

Cited by 54 publications

References 23 publications

Clinical, laboratory and molecular findings and long-term follow-up data in 96 French patients with PMM2-CDG (phosphomannomutase 2-congenital disorder of glycosylation) and review of the literature

Clinical, laboratory and molecular findings and long-term follow-up data in 96 French patients with PMM2-CDG (phosphomannomutase 2-congenital disorder of glycosylation) and review of the literature

Pharmacological Chaperoning: A Potential Treatment for PMM2-CDG

From gestalt to gene: early predictive dysmorphic features of PMM2-CDG

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